Carbapenems such as imipenem, the compound of formula (A): have a potent, broad spectrum of antibacterial activity (see U.S. Pat. Nos. 3,950,357 and 4,194,047; Merck and Co). Such carbapenems however tend to be vulnerable to hydrolysis by the enzyme renal dehydropeptidase-1 (DHP-1) and this limits their use in chemotherapy. In the case of imipenem, this problem may be overcome by the co-administration of an inhibitor of DHP-1.
Stability towards DHP-1 may also be imparted by chemical modification of the carbapenem nucleus, for instance by incorporating a 1β-methyl substitutent, as in the compound meropenem, the compound of formula (B): (see Shih D. H. et al., Heterocycles, 1984, 21, 29 and Sunagawa M. et al., J. Antibiotics, 1990, 43, 519). More recently, this has been extended to a 1β-aminoalkyl substituent (see EP 0 433 759, Bristol-Meyers Squibb).
An alternative approach to imparting improved stability to DHP-1 utilises 2-carbon substituted carbapenems, for instance, 2-aryl, 2-heteroaryl and 2-heteroaromatic carbapenems (U.S. Pat. Nos. 4,543,257, 4,260,627, 4,962,101, 4,978,659, EP 0 14 493, EP 0 414 489, EP 0 010 316 and EP 0 030 032 Merck & Co) and 2-(substituted)methyl carbapenems (Schmidt et al, J. Antibiotics, 41, 1988, 780).
UK Patent 1 593 524, Merck & Co. discloses a number of 5-membered heteroaromatic carbapenem derivatives including diazolyl and tetrazolyl compounds. However, in the case of the pyrazolyl derivatives the heterocyclic compound is attached to the carbapenem nucleus through the C-4 position.
Other structural modifications introduced at position-2 include a substituted vinyl group —C(Ra)═CHRb in which, for instance, Ra is hydrogen or methyl and Rb is hydrogen or lower alkyl (EP 0 330 108; Fujisawa) or Ra and Rb are selected from hydrogen, lower alkyl, aminocarbonyl, lower alkoxy, cyano, nitro and lower alkoxycarbonyl (EP 0 430 037, Banyu Pharmaceutical Co.). In the absence of a 1β-methyl substituent, such a modification does not however appear to impart DHP-1 stability.